CN103242274A - Beroprost sodium compound and preparation method thereof - Google Patents
Beroprost sodium compound and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a beroprost sodium compound and a preparation method thereof. The novel beroprost sodium compound and the preparation method thereof are characterized in that synthesis is carried out by selecting a mixed catalyst and optimizing reaction conditions. The beroprost sodium compound and the preparation method thereof have the advantages of high product yield, good purity, low impurities, good product stability, prolonged service life and satisfied effect.
Description
Technical field
The present invention relates to the pharmaceutical chemicals preparation field, be specifically related to a kind of Beraprost sodium compound and preparation method thereof.
Background technology
Beraprost sodium is the first oral PGI2 derivative in the whole world; has anticoagulant, vasodilation, protection vascular endothelial cell; suppress the effect of vascular smooth muscle propagation, can obviously improve the symptoms such as ulcer, intermittent claudication, pain and creeping chill that the chronic arteria occlusion disease causes.Be mainly used in peripheral vascular occlusive disease, pulmonary hypertension, arteriosclerosis, treatment of diseases such as diabetic nephropathy.Have obvious advantages such as dosage is little, rapid-action, adverse reaction rate is low.At present, beraprost sodium adopts chemical process synthetic, has deficiencies such as molar yield is low, product purity is poor, and impurity is many, and product is stable inadequately, and validity period is short in the existing synthetic method.
Summary of the invention
The present invention is for overcoming above-mentioned deficiency, the beraprost sodium synthesis technique is explored, processing parameter in the synthetic route, material proportion, reaction conditions are studied and optimized, and adopt mixed catalyst in the building-up reactions committed step, obtained a kind of new beraprost sodium two hydrates and preparation method thereof, product yield increases, product purity improves, and product impurity reduces, and product stability increases, keeping life prolongs, and has obtained promising result.
Invention embodiment is as follows:
Get 4 parts of trioxanes; 27 parts of acetic acid add 1 part of the vitriol oil, are heated to 80 ℃ under stirring; add 7-bromo-3a, 8b-cis-3a, 2 parts of 8b-dihydros-3H-5-cyclopenta benzofurancarboxylic acid; 80 ℃ were reacted 14 hours, and decompression steams acetic acid, added toluene and distilled for 10 parts; add 30 parts of ether in the residuum, crystallization filters; merge ether filtrate, concentrating under reduced pressure gets oily matter; add 20 parts of methyl alcohol, add 20 parts of 1mol/L sodium hydroxide solutions under stirring, stirring reaction is 14 hours under the room temperature; methyl alcohol is removed in decompression, adds 20 parts in water, transfers pH to 3 with 2mol/L hydrochloric acid; mixture concentrates with 10 parts of ethyl acetate extraction 3 times, filtrate, crystallization; add 10 parts of diazomethanes, reacted 2 hours, add 20 parts of ethyl acetate; 1.5 parts of sodium acetates; 0.1 part of Palladous chloride; logical hydrogen stirring reaction 2 hours filters, and adds 5 parts of saturated sodium bicarbonate solutions in the filtrate; mixed solution extracts 3 times for 10 parts with ethyl acetate, and filtrate concentrates, crystallization; add 50 parts of anhydrous tetrahydro furans; 0.01 part of Magnesium Chloride Anhydrous stirs, and adds 0.5 part of 20 parts of acetals and tosic acid; be warming up to 75 ℃, reacted 20 hours, add 0.2 part of sodium bicarbonate; at room temperature stirred 1 hour, and added 10 parts in water, mixture is extracted 3 times for 10 parts with ethyl acetate; merge organic layer, concentrate crystallization; add 100 parts of anhydrous tetrahydro furans; 0.1 part of Aluminum chloride anhydrous; 1 part of lithium aluminum hydride stirred 1 hour, the ice bath cooling; filter, concentrate, residuum adds 20 parts of dissolvings of methyl alcohol; add 4 parts in salt of wormwood, stirring at room 4 hours concentrates; residuum adds 20 parts in water, extracts 3 times for 20 parts with ethyl acetate, merges organic layer; filter, filtrate concentrates, crystallization; add 20 parts of glycol dimethyl ethers, stirring and dissolving, ice bath cooling; add 1 part of 1 part of anhydrous pyridine and thionyl chloride, stirring at room reaction 3 hours adds 10 parts of ether; precipitation is filtered, and filtrate concentrates; crystallization adds 10 parts of anhydrous tetrahydro furans; 0.1 part in magnesium; the ice bath cooling adds 0.1 part of cuprous iodide; 0.2 part of propiolactone; stirring reaction 1 hour; add 2 parts of chlorination aqueous ammoniums, transfer pH to 4 with 1mol/L hydrochloric acid, extract 5 times for 10 parts with ether; combined ether layer concentrates crystallization; 20 parts of diethyl ether solutions that add saturated diazomethane; stirring reaction 10 minutes concentrates reaction mixture, obtains oily matter; with 5 parts of dissolvings of methyl alcohol; add 2 parts of 1mol/L hydrochloric acid, mixture was at room temperature stirred 3 hours, after reaction mixture is concentrated; add 1 part in water; extract 3 times for 5 parts with ethyl acetate, the combined ethyl acetate layer, filtrate concentrates; crystallization; add 2 parts of dimethyl formamides, stirring and dissolving, ice bath cooling; add 0.2 part of 10 parts of imidazoles and tertiary butyl chloride dimethylsilane; stirring reaction 3 hours, decompression steams dimethyl formamide, obtains residuum; add 5 parts of diacetyl oxides; 5 parts of pyridines; stirring reaction 2 hours concentrates, and gets oily matter; add 5 parts of dissolvings of acetic acid; add 3 parts of tetrahydrofuran (THF)s again; 1 part in water stirred 14 hours at 50 ℃, concentrated; residuum adds 6 parts of benzene; 0.2 part of pyridine; stirring and dissolving adds 0.5 part of dimethyl sulfoxide (DMSO); 0.5 part of quadrol; 0.01 part of trifluoroacetic acid; 0.2 part of dicyclohexylcarbodiimide, stirring reaction 20 hours; precipitation; filter, filtrate concentrates, and adds 30 parts of glycol dimethyl ethers; dissolving; under argon shield, add 0.1 part of sodium hydride, 1 part of 3-methyl-2-oxo-heptan-5-alkynes-dimethyl phosphonate, stirring at room 1 hour; transfer pH to 7 with acetic acid; concentrate, residuum adds 1 part of pentane; 1 part of ether, precipitation; filter; filtrate concentrate oily matter, add 7 parts of methyl alcohol, stirring and dissolving; add 0.1 part of Cerium II Chloride; the ice bath cooling adds 0.01 part of sodium borohydride, stirs 10 minutes; add 2 parts of saturated sodium bicarbonate solutions; continue to stir 10 minutes, concentrate, residuum adds 4 parts of ethyl acetate; precipitation; filter, filtrate concentrates, and gets oily matter; add 5 parts of anhydrous methanols; stirring and dissolving adds 0.001 part of 4.8mol/L sodium methylate, stirring at room reaction 2 hours; transfer pH to 7 with acetic acid; concentrate, residuum adds 20 parts of dissolvings of ethyl acetate, filters; filtrate concentrates; get oily matter, add 5 parts of methyl alcohol, stirring and dissolving; add 1 part in 1mol/L sodium hydroxide; be warming up to 30 ℃, insulation reaction 20 hours concentrates; residuum adds 1 part in water; transfer pH to 4 with hydrochloric acid, mixture extracts 3 times for 5 parts with ethyl acetate, and filtrate concentrates; get Beraprost; add 5 parts in water, transfer pH to 8 with 1mol/L sodium hydroxide, be cooled to 2 ℃ rapidly; concentrating under reduced pressure; filter, drying gets beraprost sodium two hydrates.
The present invention program compares with prior art, and substantial characteristics and obvious improvement are:
1 selects committed step in the mixed catalyst catalytic synthesis for use, improves product yield.
2 optimize material proportion, processing parameter, reaction conditions, improve product purity.
3 obtain new beraprost sodium two hydrates, have increased the stability of product, have prolonged keeping life.
Related term is all explained with medicine related specifications such as Chinese Pharmacopoeia, State Food and Drug Administration's standards to be as the criterion if no special instructions among the present invention program.
Temperature of reaction and pressure all refer to normal temperature and pressure if no special instructions in the foregoing invention case.
" part " described in the foregoing invention scheme refers to weight part.
The raw material standard that above-mentioned embodiment is mentioned is as follows:
Trioxane: CAS number: 110-88-3; The enterprises standard;
Acetic acid: CAS number: 64-19-7; Chinese Pharmacopoeia version two ministerial standards in 2010;
Sulfuric acid: CAS number: 7664-93-9; Chinese Pharmacopoeia version two ministerial standards in 2010;
Toluene: CAS number: 108-88-3; Chinese Pharmacopoeia version two ministerial standards in 2010;
Ether: CAS number: 60-29-7; Chinese Pharmacopoeia version two ministerial standards in 2010;
Methyl alcohol: CAS number: 67-56-1; Chinese Pharmacopoeia version two ministerial standards in 2010;
Hydrochloric acid: CAS number: 7647-01-0; Chinese Pharmacopoeia version two ministerial standards in 2010;
Ethyl acetate: CAS number: 141-78-6; Chinese Pharmacopoeia version two ministerial standards in 2010;
Diazomethane: CAS number: 18107-18-1; The enterprises standard;
Sodium acetate: CAS number: 6131-90-4; Chinese Pharmacopoeia version two ministerial standards in 2010;
Palladous chloride: CAS number: 7647-10-1; The enterprises standard;
Sodium bicarbonate: CAS number: 144-55-8; Chinese Pharmacopoeia version two ministerial standards in 2010;
Sodium-chlor: CAS number: 9005-79-2; Chinese Pharmacopoeia version two ministerial standards in 2010;
Tetrahydrofuran (THF): CAS number: 109-99-9; The enterprises standard;
Acetal: CAS number: 105-57-7; The enterprises standard;
Tosic acid: CAS number: 104-15-4; The enterprises standard;
Magnesium Chloride Anhydrous: CAS number: 7791-18-6; Chinese Pharmacopoeia version two ministerial standards in 2010;
Aluminum chloride anhydrous: CAS number: 7446-70-0; Chinese Pharmacopoeia version two ministerial standards in 2010;
Benzene: CAS number: 3319-31-1; Chinese Pharmacopoeia version two ministerial standards in 2010;
Lithium aluminum hydride: CAS number: 16853-85-3; The enterprises standard;
Sodium tartrate: CAS number: 868-18-8; Chinese Pharmacopoeia version two ministerial standards in 2010;
Salt of wormwood: CAS number: 584-08-7; Chinese Pharmacopoeia version two ministerial standards in 2010;
Ethylene glycol diethyl ether: CAS number: 112-36-7; The enterprises standard;
Pyridine: CAS number: 110-86-1; Chinese Pharmacopoeia version two ministerial standards in 2010;
Magnesium: CAS number: 7439-95-4; The enterprises standard;
Cuprous iodide: CAS number: 7681-65-4; The enterprises standard;
Imidazoles: CAS number: 492-98-8; The enterprises standard;
Dimethyl formamide: CAS number: 68-12-2; The enterprises standard;
Trifluoroacetic acid: CAS number: 76-05-1; The enterprises standard;
Dimethyl sulfoxide (DMSO): CAS number: 67-68-5; The enterprises standard;
Dicyclohexylcarbodiimide: CAS number: 538-75-0; The enterprises standard;
Glycol dimethyl ether: CAS number: 534-15-6; The enterprises standard;
Cerium II Chloride: CAS number: 7790-86-5; The enterprises standard;
Sodium borohydride: CAS number: 16940-66-2; The enterprises standard;
Sodium hydroxide: CAS number: 1310-73-2; Chinese Pharmacopoeia version two ministerial standards in 2010;
7-bromo-3a, 8b-cis-3a, 8b-dihydro-3H-5-cyclopenta benzofurancarboxylic acid: enterprises standard;
Thionyl chloride: CAS number: 7719-09-7; The enterprises standard;
Propiolactone: CAS:57-57-8; The enterprises standard;
Ammonium chloride: CAS number: 12125-02-9; The enterprises standard;
Tertiary butyl chloride dimethylsilane: CAS number: 18162-48-6; The enterprises standard;
Diacetyl oxide: CAS number: 108-24-7; Chinese Pharmacopoeia version two ministerial standards in 2010;
Quadrol: CAS number: 107-15-3; Chinese Pharmacopoeia version two ministerial standards in 2010;
3-methyl-2-oxo-heptan-5-alkynes-dimethyl phosphonate: enterprises standard;
Sodium methylate: CAS number: 124-41-4; The enterprises standard;
The used raw material of above beraprost sodium does not have particular requirement, all can buy from pharmaceuticals to obtain, and all can be used to implement the present invention as long as satisfy quality standard.
Four specific embodiments
Get trioxane 4kg; acetic acid 27kg adds vitriol oil 1kg, is heated to 80 ℃ under stirring; add 7-bromo-3a, 8b-cis-3a, 8b-dihydro-3H-5-cyclopenta benzofurancarboxylic acid 2kg; 80 ℃ were reacted 14 hours, and decompression steams acetic acid, added toluene 10kg and distilled; add the 30kg ether in the residuum, crystallization filters; merge ether filtrate, concentrating under reduced pressure gets oily matter; add methyl alcohol 20kg, stir adding 1mol/L sodium hydroxide solution 20kg down, stirring reaction is 14 hours under the room temperature; methyl alcohol is removed in decompression, adds water 20kg, transfers pH to 3 with 2mol/L hydrochloric acid; mixture 10kg ethyl acetate extraction 3 times, filtrate concentrates, crystallization; add the 10kg diazomethane, reacted 2 hours, add ethyl acetate 20kg; sodium acetate 1.5kg; Palladous chloride 0.1kg; logical hydrogen stirring reaction 2 hours filters, and adds saturated sodium bicarbonate solution 5kg in the filtrate; mixed solution extracts 3 times with ethyl acetate 10kg, and filtrate concentrates, crystallization; add anhydrous tetrahydro furan 50kg; Magnesium Chloride Anhydrous 0.01kg stirs, and adds acetal 20kg and tosic acid 0.5kg; be warming up to 75 ℃, reacted 20 hours, add sodium bicarbonate 0.2kg; at room temperature stirred 1 hour, and added water 10kg, mixture is extracted 3 times with ethyl acetate 10kg; merge organic layer, concentrate crystallization; add anhydrous tetrahydro furan 100kg; Aluminum chloride anhydrous 0.1kg; lithium aluminum hydride 1kg stirred 1 hour, the ice bath cooling; filter, concentrate, residuum adds methyl alcohol 20kg dissolving; add salt of wormwood 4kg, stirring at room 4 hours concentrates; residuum adds water 20kg, extracts 3 times with ethyl acetate 20kg, merges organic layer; filter, filtrate concentrates, crystallization; add glycol dimethyl ether 20kg, stirring and dissolving, ice bath cooling; add anhydrous pyridine 1kg and thionyl chloride 1kg, stirring at room reaction 3 hours adds ether 10kg; precipitation is filtered, and filtrate concentrates; crystallization adds anhydrous tetrahydro furan 10kg; magnesium 0.1kg; the ice bath cooling adds cuprous iodide 0.1kg; propiolactone 0.2kg; stirring reaction 1 hour; add chlorination aqueous ammonium 2kg, transfer pH to 4 with 1mol/L hydrochloric acid, extract 5 times with ether 10kg; combined ether layer concentrates crystallization; the diethyl ether solution 20kg that adds saturated diazomethane; stirring reaction 10 minutes concentrates reaction mixture, obtains oily matter; dissolve with methyl alcohol 5kg; add 1mol/L hydrochloric acid 2kg, mixture was at room temperature stirred 3 hours, after reaction mixture is concentrated; add water 1kg; extract 3 times with ethyl acetate 5kg, the combined ethyl acetate layer, filtrate concentrates; crystallization; add dimethyl formamide 2kg, stirring and dissolving, ice bath cooling; add imidazoles 10kg and tertiary butyl chloride dimethylsilane 0.2kg; stirring reaction 3 hours, decompression steams dimethyl formamide, obtains residuum; add diacetyl oxide 5kg; pyridine 5kg; stirring reaction 2 hours concentrates, and gets oily matter; add acetic acid 5kg dissolving; add tetrahydrofuran (THF) 3kg again; water 1kg stirred 14 hours at 50 ℃, concentrated; residuum adds benzene 6kg; pyridine 0.2kg; stirring and dissolving adds dimethyl sulfoxide (DMSO) 0.5kg; quadrol 0.5kg; trifluoroacetic acid 0.01kg; dicyclohexylcarbodiimide 0.2kg, stirring reaction 20 hours; precipitation; filter, filtrate concentrates, and adds glycol dimethyl ether 30kg; dissolving; under argon shield, add sodium hydride 0.1kg, 3-methyl-2-oxo-heptan-5-alkynes-dimethyl phosphonate 1kg, stirring at room 1 hour; transfer pH to 7 with acetic acid; concentrate, residuum adds pentane 1kg; ether 1kg, precipitation; filter; filtrate concentrate oily matter, add methyl alcohol 7kg, stirring and dissolving; add Cerium II Chloride 0.1kg; the ice bath cooling adds sodium borohydride 0.01kg, stirs 10 minutes; add saturated sodium bicarbonate solution 2kg; continue to stir 10 minutes, concentrate, residuum adds ethyl acetate 4kg; precipitation; filter, filtrate concentrates, and gets oily matter; add anhydrous methanol 5kg; stirring and dissolving adds 4.8mol/L sodium methylate 0.001kg, stirring at room reaction 2 hours; transfer pH to 7 with acetic acid; concentrate, residuum adds ethyl acetate 20kg dissolving, filters; filtrate concentrates; get oily matter, add methyl alcohol 5kg, stirring and dissolving; add 1mol/L sodium hydroxide 1kg; be warming up to 30 ℃, insulation reaction 20 hours concentrates; residuum adds water 1kg; transfer pH to 4 with hydrochloric acid, mixture extracts 3 times with ethyl acetate 5kg, and filtrate concentrates; get Beraprost; add water 5kg, transfer pH to 8 with 1mol/L sodium hydroxide, be cooled to 2 ℃ rapidly; concentrating under reduced pressure; filter, drying gets beraprost sodium two hydrates.
The specific embodiment explanation adopts embodiment of the present invention can make beraprost sodium two hydrates, and the beraprost sodium that makes with embodiment is investigated actual effect of the present invention below:
1 the present invention program prepares beraprost sodium and prepares the contrast of beraprost sodium product purity with adopting art methods.
Table 1 purity contrast table
The above results shows, the present invention prepares beraprost sodium and significantly improves than adopting art methods and preparing the beraprost sodium product purity.
2 the present invention program prepare beraprost sodium and prepare the contrast of beraprost sodium total impurities with adopting art methods.
Table 2 total impurities contrast table
The above results shows, the present invention prepares beraprost sodium and significantly reduces than adopting art methods and prepare beraprost sodium and producing total impurities.
3 the present invention program prepare beraprost sodium and prepare the total molar yield contrast of beraprost sodium with adopting art methods.
The total molar yield contrast table of table 3
The above results shows, the present invention prepares beraprost sodium and significantly improves than adopting art methods and preparing the total molar yield of beraprost sodium.
4 the present invention program prepare beraprost sodium and adopt the contrast of prior art for preparing beraprost sodium validity period.
Method:
Get the Beraprost sodium sample of the present invention program's preparation and the Beraprost sodium sample of prior art for preparing and place 25 ℃ ± 2 ℃ of temperature, in RH60% ± 10% environment, in the 0th, 3,6,9,12,18,24,36 sampling at the end of month, detect according to the beraprost sodium standards project.
The result:
Table 4 validity period contrast table
The above results shows that the present invention prepares beraprost sodium than adopting prior art for preparing beraprost sodium valid period significant prolongation, and stability increases.
The beraprost sodium safety testing of 5 invention schemes preparation.
Method:
Test according to " chemicals is acute, long term toxicity investigative technique governing principle " appended method that State Food and Drug Administration announces.
The result:
The beraprost sodium of the present invention program's preparation is not found acute, long term toxicity reaction to the test white mouse, acts on safe and reliable.
Claims (2)
1. a Beraprost sodium compound is characterized in that getting 4 parts of trioxanes; 27 parts of acetic acid add 1 part of the vitriol oil; be heated to 80 ℃ under stirring, add 7-bromo-3a, 8b-cis-3a; 2 parts of 8b-dihydros-3H-5-cyclopenta benzofurancarboxylic acid, 80 ℃ of reactions 14 hours, decompression steams acetic acid; add toluene and distill for 10 parts, add 30 parts of ether, crystallization in the residuum; filter, merge ether filtrate, concentrating under reduced pressure; get oily matter, add 20 parts of methyl alcohol, add 20 parts of 1mol/L sodium hydroxide solutions under stirring; stirring reaction is 14 hours under the room temperature, and methyl alcohol is removed in decompression, adds 20 parts in water; transfer pH to 3 with 2mol/L hydrochloric acid, mixture is with 10 parts of ethyl acetate extraction 3 times, and filtrate is concentrated; crystallization adds 10 parts of diazomethanes, reacts 2 hours; add 20 parts of ethyl acetate; 1.5 parts of sodium acetates; 0.1 part of Palladous chloride, logical hydrogen stirring reaction 2 hours filters; add 5 parts of saturated sodium bicarbonate solutions in the filtrate, mixed solution extracts 3 times for 10 parts with ethyl acetate, and filtrate concentrates; crystallization adds 50 parts of anhydrous tetrahydro furans; 0.01 part of Magnesium Chloride Anhydrous stirs; add 0.5 part of 20 parts of acetals and tosic acid, be warming up to 75 ℃, reacted 20 hours; add 0.2 part of sodium bicarbonate, at room temperature stirred 1 hour, add 10 parts in water; mixture is extracted 3 times for 10 parts with ethyl acetate, merge organic layer, concentrate; crystallization adds 100 parts of anhydrous tetrahydro furans; 0.1 part of Aluminum chloride anhydrous; 1 part of lithium aluminum hydride stirred 1 hour; the ice bath cooling is filtered, and concentrates; residuum adds 20 parts of dissolvings of methyl alcohol, adds 4 parts in salt of wormwood, stirring at room 4 hours; concentrate, residuum adds 20 parts in water, extracts 3 times for 20 parts with ethyl acetate; merge organic layer, filter, filtrate concentrates; crystallization adds 20 parts of glycol dimethyl ethers, stirring and dissolving; the ice bath cooling adds 1 part of 1 part of anhydrous pyridine and thionyl chloride, stirring at room reaction 3 hours; add 10 parts of ether, precipitation is filtered; filtrate concentrates, and crystallization adds 10 parts of anhydrous tetrahydro furans; 0.1 part in magnesium; the ice bath cooling; add 0.1 part of cuprous iodide; 0.2 part of propiolactone; stirring reaction 1 hour adds 2 parts of chlorination aqueous ammoniums, transfers pH to 4 with 1mol/L hydrochloric acid; extract 5 times for 10 parts with ether, combined ether layer concentrates; crystallization adds 20 parts of the diethyl ether solutions of saturated diazomethane, stirring reaction 10 minutes; reaction mixture is concentrated; obtain oily matter, with 5 parts of dissolvings of methyl alcohol, add 2 parts of 1mol/L hydrochloric acid; mixture was at room temperature stirred 3 hours; after reaction mixture is concentrated, add 1 part in water, extract 3 times for 5 parts with ethyl acetate; the combined ethyl acetate layer; filtrate concentrates, and crystallization adds 2 parts of dimethyl formamides; stirring and dissolving; the ice bath cooling adds 0.2 part of 10 parts of imidazoles and tertiary butyl chloride dimethylsilane, stirring reaction 3 hours; decompression steams dimethyl formamide; obtain residuum, add 5 parts of diacetyl oxides; 5 parts of pyridines, stirring reaction 2 hours; concentrate; get oily matter, add 5 parts of dissolvings of acetic acid, add 3 parts of tetrahydrofuran (THF)s again; 1 part in water; stirred 14 hours at 50 ℃; concentrate, residuum adds 6 parts of benzene; 0.2 part of pyridine, stirring and dissolving; add 0.5 part of dimethyl sulfoxide (DMSO); 0.5 part of quadrol; 0.01 part of trifluoroacetic acid; 0.2 part of dicyclohexylcarbodiimide; stirring reaction 20 hours, precipitation is filtered; filtrate concentrates; add 30 parts of glycol dimethyl ethers, dissolving adds 0.1 part of sodium hydride under argon shield; 1 part of 3-methyl-2-oxo-heptan-5-alkynes-dimethyl phosphonate; stirring at room 1 hour is transferred pH to 7 with acetic acid, concentrates; residuum adds 1 part of pentane; 1 part of ether; precipitation is filtered, filtrate concentrate oily matter; add 7 parts of methyl alcohol; stirring and dissolving adds 0.1 part of Cerium II Chloride, the ice bath cooling; add 0.01 part of sodium borohydride; stirred 10 minutes, and added 2 parts of saturated sodium bicarbonate solutions, continue to stir 10 minutes; concentrate; residuum adds 4 parts of ethyl acetate, and precipitation is filtered; filtrate concentrates; get oily matter, add 5 parts of anhydrous methanols, stirring and dissolving; add 0.001 part of 4.8mol/L sodium methylate; stirring at room reaction 2 hours is transferred pH to 7 with acetic acid, concentrates; residuum adds 20 parts of dissolvings of ethyl acetate; filter, filtrate concentrates, and gets oily matter; add 5 parts of methyl alcohol; stirring and dissolving adds 1 part in 1mol/L sodium hydroxide, is warming up to 30 ℃; insulation reaction 20 hours; concentrate, residuum adds 1 part in water, transfers pH to 4 with hydrochloric acid; mixture extracts 3 times for 5 parts with ethyl acetate; filtrate concentrates, and gets Beraprost, adds 5 parts in water; transfer pH to 8 with 1mol/L sodium hydroxide; be cooled to 2 ℃ rapidly, concentrating under reduced pressure filters; drying gets beraprost sodium two hydrates.
2. according to the preparation method of the described Beraprost sodium compound of claim 1, it is characterized in that getting 4 parts of trioxanes; 27 parts of acetic acid add 1 part of the vitriol oil; be heated to 80 ℃ under stirring, add 7-bromo-3a, 8b-cis-3a; 2 parts of 8b-dihydros-3H-5-cyclopenta benzofurancarboxylic acid, 80 ℃ of reactions 14 hours, decompression steams acetic acid; add toluene and distill for 10 parts, add 30 parts of ether, crystallization in the residuum; filter, merge ether filtrate, concentrating under reduced pressure; get oily matter, add 20 parts of methyl alcohol, add 20 parts of 1mol/L sodium hydroxide solutions under stirring; stirring reaction is 14 hours under the room temperature, and methyl alcohol is removed in decompression, adds 20 parts in water; transfer pH to 3 with 2mol/L hydrochloric acid, mixture is with 10 parts of ethyl acetate extraction 3 times, and filtrate is concentrated; crystallization adds 10 parts of diazomethanes, reacts 2 hours; add 20 parts of ethyl acetate; 1.5 parts of sodium acetates; 0.1 part of Palladous chloride, logical hydrogen stirring reaction 2 hours filters; add 5 parts of saturated sodium bicarbonate solutions in the filtrate, mixed solution extracts 3 times for 10 parts with ethyl acetate, and filtrate concentrates; crystallization adds 50 parts of anhydrous tetrahydro furans; 0.01 part of Magnesium Chloride Anhydrous stirs; add 0.5 part of 20 parts of acetals and tosic acid, be warming up to 75 ℃, reacted 20 hours; add 0.2 part of sodium bicarbonate, at room temperature stirred 1 hour, add 10 parts in water; mixture is extracted 3 times for 10 parts with ethyl acetate, merge organic layer, concentrate; crystallization adds 100 parts of anhydrous tetrahydro furans; 0.1 part of Aluminum chloride anhydrous; 1 part of lithium aluminum hydride stirred 1 hour; the ice bath cooling is filtered, and concentrates; residuum adds 20 parts of dissolvings of methyl alcohol, adds 4 parts in salt of wormwood, stirring at room 4 hours; concentrate, residuum adds 20 parts in water, extracts 3 times for 20 parts with ethyl acetate; merge organic layer, filter, filtrate concentrates; crystallization adds 20 parts of glycol dimethyl ethers, stirring and dissolving; the ice bath cooling adds 1 part of 1 part of anhydrous pyridine and thionyl chloride, stirring at room reaction 3 hours; add 10 parts of ether, precipitation is filtered; filtrate concentrates, and crystallization adds 10 parts of anhydrous tetrahydro furans; 0.1 part in magnesium; the ice bath cooling; add 0.1 part of cuprous iodide; 0.2 part of propiolactone; stirring reaction 1 hour adds 2 parts of chlorination aqueous ammoniums, transfers pH to 4 with 1mol/L hydrochloric acid; extract 5 times for 10 parts with ether, combined ether layer concentrates; crystallization adds 20 parts of the diethyl ether solutions of saturated diazomethane, stirring reaction 10 minutes; reaction mixture is concentrated; obtain oily matter, with 5 parts of dissolvings of methyl alcohol, add 2 parts of 1mol/L hydrochloric acid; mixture was at room temperature stirred 3 hours; after reaction mixture is concentrated, add 1 part in water, extract 3 times for 5 parts with ethyl acetate; the combined ethyl acetate layer; filtrate concentrates, and crystallization adds 2 parts of dimethyl formamides; stirring and dissolving; the ice bath cooling adds 0.2 part of 10 parts of imidazoles and tertiary butyl chloride dimethylsilane, stirring reaction 3 hours; decompression steams dimethyl formamide; obtain residuum, add 5 parts of diacetyl oxides; 5 parts of pyridines, stirring reaction 2 hours; concentrate; get oily matter, add 5 parts of dissolvings of acetic acid, add 3 parts of tetrahydrofuran (THF)s again; 1 part in water; stirred 14 hours at 50 ℃; concentrate, residuum adds 6 parts of benzene; 0.2 part of pyridine, stirring and dissolving; add 0.5 part of dimethyl sulfoxide (DMSO); 0.5 part of quadrol; 0.01 part of trifluoroacetic acid; 0.2 part of dicyclohexylcarbodiimide; stirring reaction 20 hours, precipitation is filtered; filtrate concentrates; add 30 parts of glycol dimethyl ethers, dissolving adds 0.1 part of sodium hydride under argon shield; 1 part of 3-methyl-2-oxo-heptan-5-alkynes-dimethyl phosphonate; stirring at room 1 hour is transferred pH to 7 with acetic acid, concentrates; residuum adds 1 part of pentane; 1 part of ether; precipitation is filtered, filtrate concentrate oily matter; add 7 parts of methyl alcohol; stirring and dissolving adds 0.1 part of Cerium II Chloride, the ice bath cooling; add 0.01 part of sodium borohydride; stirred 10 minutes, and added 2 parts of saturated sodium bicarbonate solutions, continue to stir 10 minutes; concentrate; residuum adds 4 parts of ethyl acetate, and precipitation is filtered; filtrate concentrates; get oily matter, add 5 parts of anhydrous methanols, stirring and dissolving; add 0.001 part of 4.8mol/L sodium methylate; stirring at room reaction 2 hours is transferred pH to 7 with acetic acid, concentrates; residuum adds 20 parts of dissolvings of ethyl acetate; filter, filtrate concentrates, and gets oily matter; add 5 parts of methyl alcohol; stirring and dissolving adds 1 part in 1mol/L sodium hydroxide, is warming up to 30 ℃; insulation reaction 20 hours; concentrate, residuum adds 1 part in water, transfers pH to 4 with hydrochloric acid; mixture extracts 3 times for 5 parts with ethyl acetate; filtrate concentrates, and gets Beraprost, adds 5 parts in water; transfer pH to 8 with 1mol/L sodium hydroxide; be cooled to 2 ℃ rapidly, concentrating under reduced pressure filters; drying gets beraprost sodium two hydrates.
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| US10577341B1 (en) * | 2018-11-26 | 2020-03-03 | Chirogate International Inc. | Beraprost-314d monohydrate crystals and methods for preparation thereof |
| CN112480049A (en) * | 2020-12-27 | 2021-03-12 | 河南师范大学 | Synthetic method of indeno [1,2-c ] furan compound |
| CN115872962A (en) * | 2023-01-06 | 2023-03-31 | 成都硕德药业有限公司 | Beraprost sodium intermediate and preparation method thereof |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10577341B1 (en) * | 2018-11-26 | 2020-03-03 | Chirogate International Inc. | Beraprost-314d monohydrate crystals and methods for preparation thereof |
| CN112480049A (en) * | 2020-12-27 | 2021-03-12 | 河南师范大学 | Synthetic method of indeno [1,2-c ] furan compound |
| CN112480049B (en) * | 2020-12-27 | 2023-09-08 | 河南师范大学 | Synthesis method of indenone [1,2-c ] furan compound |
| CN115872962A (en) * | 2023-01-06 | 2023-03-31 | 成都硕德药业有限公司 | Beraprost sodium intermediate and preparation method thereof |
| CN115872962B (en) * | 2023-01-06 | 2023-04-28 | 成都硕德药业有限公司 | Beraprost sodium intermediate and preparation method thereof |
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| CN103242274B (en) | 2014-11-05 |
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